Recent advances in sequencing technology have allowed scientists to draw connections between the microbial communities on and within the human body and many human health conditions. Yet, one of the key challenges for the future is translating knowledge gained from these sequencing studies into effective therapies. Periodontitis is a major disease of the oral cavity that affects 65 million Americans. Metagenomic and metatranscriptomic studies have identified specific metabolic shifts within microbial communities associated with periodontal disease that include increases in ribosome content as well as in expression of genes for amino acid degradation and fermentation, purine and tetrahydrofolate biosynthesis, and iron and cobalamin transport. Non-coding RNA (ncRNA) regulators such as riboswitches play key roles in regulating bacterial metabolism, and are the targets of both existing and novel antimicrobials. Furthermore, riboswitches control several of the upregulated pathways associated with periodontal disease in many bacterial species. However, most studies of the human microbiome focus on the composition of microbial communities and their complement of protein encoding genes, but have not examined how these genes are regulated. The objective of this proposal is to determine whether the specific metabolic changes associated with periodontal disease are mediated by RNA regulators. To achieve this objective we have two specific aims. First, to determine whether the metabolic shifts associated with periodontitis are directly subject to riboswitch control. Second, to identif RNA regulators of ribosomal protein synthesis in the phylum Bacteroidetes (including species of the genera Prevotella, Porphyromonas, and Tannerella) that are overrepresented in periodontitis associated communities. To accomplish these goals, RNA-specific homology search and de novo discovery tools will be applied to the reference genomes in the Human Oral Microbiome Database (HOMD), existing metagenomic data from the Human Microbiome Project (HMP) and other studies, and metatranscriptomic data from the oral microbiome. Computational analysis of ncRNAs will be followed by experimental validation of specific targets using in vitro approaches. The proposed work will determine whether antimicrobials already in development may be utilized to control periodontitis associated microbial communities. Furthermore, this research is expected to uncover additional targets for the development of novel antimicrobials. This will lead directly toward a greater fundamental understanding of the driving factors behind the metabolic shifts associated with periodontal disease so that these shifts, rather than the organisms behind them, may be targeted.